Effects of the kappa opioid receptor antagonist nor‐binaltorphimine (nor‐<scp>BNI</scp>) on cocaine versus food choice and extended‐access cocaine intake in rhesus monkeys

Drug and Alcohol Dependence

2016

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Background Clinical trial data suggest amphetamine treatment is most efficacious in moderate to high frequency cocaine users. However, preclinical studies have examined amphetamine treatment effects under relatively limited cocaine access conditions with low to moderate cocaine intakes. This study determined d-amphetamine treatment effects on cocaine self-administration in rhesus monkeys under cocaine access conditions allowing for high daily cocaine intake. For comparison and as a negative control, treatment effects with the antipsychotic risperidone were also examined. Methods Continuous 21-day treatments with ramping doses of d-amphetamine (days 1–7: 0.032 mg/kg/h; days 8–21: 0.1 mg/kg/h, i.v.) or risperidone (days 1–7: 0.001 mg/kg/h; days 8–14: 0.0032 mg/kg/h; days 15–21: 0.0056 mg/kg/h, i.v.) were administered to rhesus monkeys (n = 4) with daily access to two types of cocaine self-administration sessions: (1) a 2-h ‘choice’ session with concurrent availability of 1-g food pellets and intravenous cocaine injections (0–0.1 mg/kg per injection) and (2) a 20-h ‘extended-access’ session with 0.1 mg/kg per injection cocaine availability. Results Total daily cocaine intake increased >6-fold during extended cocaine access. d-Amphetamine significantly decreased total cocaine intake, but not cocaine vs food choice. In contrast, risperidone did not significantly alter either total cocaine intake or cocaine vs. food choice. Conclusions These results confirm and extend previous results supporting treatment effectiveness for monoamine releasers, but not dopamine antagonists, to reduce cocaine self-administration. Moreover, these results suggest amphetamine treatment efficacy to decrease preclinical cocaine vs. food choice may depend upon cocaine access conditions.

Section: Discussionsupporting

confidence: 91%

“…All subjects had prior cocaine self-administration histories (Banks et al, 2013a; Hutsell et al, 2016). Monkeys weighed 9–13 kg and were maintained on a diet of fresh fruit and food biscuits (Lab Diet High Protein Monkey Biscuits no.…”

Section: Methodsmentioning

confidence: 99%

Effects of 21-day d -amphetamine and risperidone treatment on cocaine vs food choice and extended-access cocaine intake in male rhesus monkeys

Hutsell

Negus

Drug and Alcohol Dependence

2016

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“…We have shown previously that norBNI alone does not alter cocaine vs. food choice (Hutsell et al, 2016; Negus, 2004), and the dose of norBNI used in the present study (10 mg/kg) has been shown previously to produce selective kappa antagonist effects for up to two weeks (Ko et al, 1998). Taken together, these results suggest that kappa receptor antagonism is not sufficient to enhance amphetamine-induced reductions in cocaine vs. food choice, and provide further support for the conclusion that effects of naltrexone were mediated by its antagonism of mu rather than kappa receptors.…”

Section: Discussionsupporting

confidence: 50%

“…Finally, the effects of 0.032 mg/kg/h amphetamine were also determined alone or in combination with the kappa antagonist norbinaltorphimine (norBNI) (10 mg/kg administered IM once on the first day of amphetamine treatment). The single-dose treatment regimen was based on previous studies to indicate that 10 mg/kg norBNI produces kappa antagonist effects for at least two weeks and does not alter cocaine vs. food choice when administered alone (Hutsell et al, 2016; Ko et al, 1998; Negus, 2004). Only one monkey received all treatments; other monkeys exhausted their catheterization sites, and these monkeys had to be replaced over the course of the study.…”

Section: Methodsmentioning

confidence: 99%

Maintenance on naltrexone + amphetamine decreases cocaine-vs.-food choice in male rhesus monkeys

Moerke

Drug and Alcohol Dependence

Cheng

et al. 2017

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Background Cocaine use disorder remains a significant public health issue for which there are no FDA-approved pharmacotherapies. Amphetamine maintenance reduces cocaine use in preclinical and clinical studies, but the mechanism of this effect is unknown. Previous studies indicate a role for endogenous opioid release and subsequent opioid receptor activation in some amphetamine effects; therefore, the current study examined the role of mu-opioid receptor activation in d-amphetamine treatment effects in an assay of cocaine-vs-food choice. Methods Adult male rhesus monkeys with double-lumen intravenous catheters responded for concurrently available food pellets and cocaine injections (0–0.1 mg/kg/injection) during daily sessions. Cocaine choice and overall reinforcement rates were evaluated during 7-day treatments with saline or test drugs. Results During saline treatment, cocaine maintained a dose-dependent increase in cocaine-vs.-food choice. The mu-opioid receptor agonist morphine (0.032–0.32 mg/kg/h) dose-dependently increased cocaine choice and decreased rates of reinforcement. A dose of the mu-selective opioid receptor antagonist naltrexone (0.0032 mg/kg/h) that completely blocked morphine effects had no effect on cocaine choice when it was administered alone, but it enhanced the effectiveness of a threshold dose of 0.032 mg/kg/h amphetamine to decrease cocaine choice without also enhancing nonselective behavioral disruption by this dose of amphetamine. Conversely, the kappa-selective opioid antagonist norbinalorphimine did not enhance amphetamine effects on cocaine choice. Conclusions These results suggest that amphetamine maintenance produces mu opioid-receptor mediated effects that oppose its anti-cocaine effects. Co-administration of naltrexone may selectively enhance amphetamine potency to decrease cocaine choice without increasing amphetamine potency to produce general behavioral disruption.

“…However, when acute nor-BNI treatment was evaluated under drug self-administration conditions that included an alternative, nondrug reinforcer, it failed to attenuate either cocaine versus food choice [82,83] or methamphetamine versus food choice (Banks, unpublished observations, XXXX) in nonhuman primates. Furthermore, acute treatment with another long-acting KOR antagonist, 5′-guanidonaltrindole, also failed to block withdrawal-associated increases in heroin versus food choice in nonhuman primates [84].…”

Section: Pharmacological Determinantsmentioning

confidence: 99%

Insights from Preclinical Choice Models on Treating Drug Addiction

Trends in Pharmacological Sciences

Negus

2017

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109

Substance-use disorders are a global public health problem that arises from behavioral misallocation between drug use and more adaptive behaviors maintained by nondrug alternatives (e.g., food or money). Preclinical drug self-administration procedures that incorporate a concurrently available nondrug reinforcer (e.g., food) provide translationally relevant and distinct dependent measures of behavioral allocation (i.e., to assess the relative reinforcing efficacy of the drug) and behavioral rate (i.e., to assess motor competence). In particular, preclinical drug versus food 'choice' procedures have produced increasingly concordant results with both human laboratory drug self-administration studies and double-blind placebo-controlled clinical trials. Accordingly, here we provide a heuristic framework of substance-use disorders based on a behavioral-centric perspective and recent insights from these preclinical choice procedures. Keywordschoice; addiction; preclinical model; drug self-administration; substance-use disorder Trends Substance-use disorders (i.e., drug addiction) are increasingly being conceptualized as disorders of behavioral misallocation between drug and nondrug reinforcers.Preclinical drug versus food choice procedures are increasingly being utilized to elucidate environmental, pharmacological, and biological mechanisms associated with this behavioral misallocation.Preclinical drug versus food choice procedures provide distinct dependent measures that dissociate drug reinforcement (i.e., allocation of behavior) from motor competence (i.e., rate of behavior). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptAlternative nondrug reinforcer availability and temporal delivery impact behavioral allocation.Preclinical drug versus food choice procedures are being developed for abused drugs other than cocaine.Biological variables are an emerging as important determinants of behavioral allocation between drug and nondrug reinforcers. Drug AddictionDrug addiction is an insidious and global public health problem. . Furthermore, six of the 11 diagnostic criteria used for substance-use disorders are based on the allocation of behavior towards the procurement and use of the substance compared with other behaviors maintained by nondrug and presumably more adaptive alternative reinforcers (e.g., food, money, or social commendation). Thus, the diagnosis of substance-use disorders takes a behavioral-centric perspective and implies that such disorders arise from behavioral misallocat...